Regulation of β-Adrenergic Receptor Signaling by S-Nitrosylation of G-Protein-Coupled Receptor Kinase 2

Abstract

beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent the loss of beta-AR signaling in vivo, but the molecular details are unknown. Here we show in mice that SNOs increase beta-AR expression and prevent agonist-stimulated receptor downregulation; and in cells, SNOs decrease GRK2-mediated beta-AR phosphorylation and subsequent recruitment of beta-arrestin to the receptor, resulting in the attenuation of receptor desensitization and internalization. In both cells and tissues, GRK2 is S-nitrosylated by SNOs as well as by NO synthases, and GRK2 S-nitrosylation increases following stimulation of multiple GPCRs with agonists. Cys340 of GRK2 is identified as a principal locus of inhibition by S-nitrosylation. Our studies thus reveal a central molecular mechanism through which GPCR signaling is regulated.

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…These findings highlight the compartmentalized and targeted actions of NOS enzymes, and their specific S-nitrosylation of effector proteins that include NMDA and ryanodine receptor, G-protein coupled receptor kinase 2, caspases, GAPDH, NSF, dynamin, cycooxygenase 2 [1,58,80], and many other protein targets. S-nitrosylation also is known to affect the function of molecular chaperones, and this paradigm plays a central role in the regulation of apoptosis.…”

“…GSNO reductase knock-out mice were also hypotensive under anesthesia and showed enhanced susceptibility to mortality from endotoxin or septic shock [9]. GSNO reductase activity also has been linked to β-adrenergic receptor signaling via its regulation of S-nitrosylation state of G-protein coupled receptor kinase-2 [80], a central mediator of GPCR densensitization. Intriguingly, polymorphisms in the GSNO reductase gene were recently identified and demonstrated correlations with asthma susceptibility [81].…”

Beta Adrenoceptor Polymorphism and Clinical Response to Sertraline in Major Depressive Patients

“…Although many studies bold the contribution of genetics in predisposition to MDD, its role as therapeutic determinant remains obscure. β 1 ARsbelong to the family of GPCRs representing the leading target for modern drug therapy (38). GPCRs is a foremost contributor to the pathophysiology of several mental illnesses (39,40) .…”

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

“…S-nitrosylation of myocardial target proteins associated with ␤-adrenergic receptor signaling and/or calcium handling influences the contraction of the heart (31,54,69). In regard to pathophysiology, increasing the S-nitrosylation of proteins during myocardial I/R can attenuate a number of adverse processes (10,36,64), such as apoptosis (46) and inflammation (14), and even stimulate protective processes like angiogenesis (45).…”